Lupus erythematosus is a disease that affects primarily young women. Its pathology is mediated to a large extent by the loss of regulatory mechanisms in B cells. More than 50 gene polymorphisms have been associated with increased risk for systemic lupus, many of them related to B cell function, but the mechanisms by which these variants increase disease susceptibility is still unknown. This is a revision for an application for a K01 award for Dr. Manjarrez-Orduo designed to help her make the transition to an independent investigator, able to propose therapeutic targets for deregulated molecular interactions in systemic lupus based on an understanding of the functional consequences of genetic variation in B cells. This proposal will provide Dr. Manjarrez-Orduo with training in (1) genetics and genomics, (2) statistical methods, and (3) B cell biology. The achievement of these goals will be accomplished with cross-disciplinary mentorship led by Dr. Betty Diamond who will provide with expertise on autoimmune diseases and B cell biology, and Dr. Peter K. Gregersen who will manage the training in genetics and biological network analysis. The aim of this proposal is to understand how Csk controls antibody responses by its regulation of the B cell receptor (BCR) both during B cell maturation and activation. Specifically, we will determine whether Csk-mediated regulation of the B cell signaling perturbs the conditions for the development of tolerance during maturation of transitional cells (Aim 1); next, we will focus on nave B cells to generate evidence that higher Csk expression leads to BCR hyper-responsiveness mediated by CD22 and FcR?IIb (Aim 2) and finally we will prove that these two events converge in the generation of an autoreactive repertoire (Aim 3), setting the conditions for the development of autoimmune disease. Because this project focuses on events that happen in human cells, it will generate knowledge that is directly translatable into human disease and therapy. The data generated should allow Dr. Manjarrez- Orduo to compete for R01 funding before the end of this training period.